NHE3 is found in the body of various species, for example, in the gall bladder, the intestine and the kidney (Larry Fliegel et al., Biochem. Cell. Biol. 76: 735-741, 1998), but can also be detected in the brain (E. Ma et al., Neuroscience 79: 591-603).
The NHE3 inhibitors known to date are derived from compounds of the acylguanidine type (EP825178), of the norbornylamine type (DE1 99 60 204), of the 2-guanidino-quinazoline type (WO 0179186) or of the benzamidine type (WO0121582, WO0172742). Squalamine, which has also been described as NHE3 inhibitor (M. Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144), is, according to current understanding, not, unlike the compounds of formula I, effective immediately, but rather via an indirect mechanism and thus reaches its maximum potency only after one hour. Such NHE3 inhibitors which act by a different mechanism are therefore suitable for use as combination partners for the present compounds according to the invention.
Clonidine, which is similar to the compounds described here, is known as a weak NHE inhibitor. However, its action on the NHE3 of the rat is, with a half-maximal inhibitory concentration (IC50) of 620 μM, extremely moderate. In contrast, it shows a certain selectivity for the NHE2 (J. Orlowski et al. J. Biol. Chem. 268, 25536). It would therefore be more accurate to refer to clonidine as an NHE2 inhibitor. In addition to the weak NHE action, clonidine has a high affinity for the adrenergic alpha2 receptor and the imidazoline I1 receptor, mediating a strong hypotensive action (Ernsberger et al., Eur. J. Pharmacol. 134, 1, 1987).
Clonidine-like compounds having a thiophene ring instead of the phenyl ring are known from DE1941761. These known compounds differ from the structures of formula I described in the present invention in that they have considerably smaller radicals R7 and R8 and in particular by the fact that R7 and R8 are not capable of forming a joint ring.
By these differences in the substituents R7 and R8, it is possible to eliminate the undesirable clonidine-like cardiovascular effects described above, which are mediated by the alpha-adrenoceptor action. At the same time, owing to these differences in the substituents, the NHE-inhibiting properties of the compounds described herein are enhanced to the micromolar and submicromolar range, whereas the compounds known from DE1941761 show only extremely weak NHE-inhibiting effects, if any.
The present invention provides a different kind of NHE3 inhibitors.